Animal models of amphetamine have focused largely on stereotypy, i.e., amphetamine's capacity to induce stereotyped movements (sniffing, licking, chewing), and these models have been widely used to develop antipsychotic drugs. Drugs selected in this way have consistently implicated dopamine transmitter systems in psychosis and have almost invariably had extrapyramidal (motor) side effects. However, recent biochemical evidence has implicated other transmitter systems and has raised the possibility of achieving antipsychotic effects without extrapyramidal motor effects. In view of this biochemical evidence, there is a need for animal behavior models that focus on behavior other than stereotypy. We have recently developed a model based on the rat's natural defense response of flight. In this procedure the rat is placed on a slow-moving treadmill that carries it toward a novel stimulus; to avoid the stimulus the rat must execute a continuously active flight response. Rats given chronic saline treatment showed no tendency to flee from the stimulus, but rats given chronic (2-week) amphetamine treatment showed a dramatic and significant flight response. The amphetamine-treated rats showed some extrapyramidal motor effects (stereotypy) in both stimulus and control tests, but showed the full flight response only in the presence of the novel stimulus. Thus, the defense response of flight has the advantage of being a simple, robust response that can be executed despite extrapyramidal motor effects. The objective of the proposed research is to evaluate the defense response of flight as a model for amphetamine psychosis. As a valid model the behavior must respond to drug treatment in accord with established criteria. Specifically, chronic amphetamine treatment should affect the defense response of flight with: 1) an augmentation of effects produced by acute treatment, 2) a predictable development of effects over time, 3) carryover effects that potentiate subsequent drug response, and 4) antagonism by known antipsychotic drugs. If the defense response of flight satisfies these criteria it may prove to be an evaluable model for the development of antipsychotic drugs, and it may provide useful clues to the neuropharmacological mediation of amphetamine psychosis.